Malaria and other parasitic diseases are serious public health problems. The known antimalarial agent, mefloquine, and its analogs have serious side effects including depression, psychotic episodes, and suicidal episodes. Because of these serious side effects, there have been attempts to formulate alternative antiparasitic compounds. Several approaches have attempted to use a quinoline structure and the primaquine branched 8-amino(1-alkyl)amino group. U.S. Pat. No. 4,980,360 discloses quinoline compounds having the primaquine 8-amino-1-methylbutylamino group which are reported for malaria treatment. U.S. Pat. Nos. 4,431,807 and 4,617,394 disclose quinoline compounds having a primaquine-like branched 8-aminoalkylamino group which are reported for treatment of malaria. U.S. Pat. No. 7,145,014 discloses quinoline compounds having an 8-[(4-amino-1-methylbutyl(amino) group. U.S. Pat. No. 6,376,511 discloses certain branched 8-aminoquinolines for the treatment of parasitic infections. U.S. Pat. No. 6,479,660 discloses methods of making certain antimalarial drugs. Other quinolines designed for the treatment of malaria are described in LaMontagne, J. Med. Chem. 1989, 32, 1728-1732.
Until recently, there was little information on the link between the structure of these antimalarial drugs and their detrimental psychological properties. It was discovered recently that mefloquine inhibits gap junctions, such as connexins 50 (Cx50). Gap junctions are the electrical synapses in neurons and responsible for neural transmission. They are non-specific membrane channels between cells and allow the passage of small molecules and ions from one cell to the next. Most tissues are coupled together by gap junctions that vary in type from cell to cell. Gap junctions are made up of hexamers of gap junction proteins, called connexins, abbreviated as Cx and named for their approximate size. Each hexamer hemichannel docks to another on an adjacent cell to form a complete channel or connexin. Connexin mutations have led to a number of human diseases, such as neurosensory autosomal recessive deafness, and the development of cardiovascular abnormalities.
The disruption of gap junctions produces serious neurological effects and is seen in neurodegenerative diseases such as Parkinson's disease and psychological diseases. Gap junction inhibitors are used to treat ischemic injury, such as stroke or during retinal surgery. Most, if not all, tumor cells have dysfunctional gap junctional intercellular communication (GJIC). Restoring GJIC is linked to drug sensitivity and reduction of tumorigenicity. The information regarding gap junction activity should be useful in development of new compounds that can be used to restore gap junction communication, or inhibit gap junction communication, depending on the disruption. New compounds that affect gap junctions are needed.